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Original Investigation |

Age-Dependent Effects of Methylphenidate on the Human Dopaminergic System in Young vs Adult Patients With Attention-Deficit/Hyperactivity Disorder A Randomized Clinical Trial

Anouk Schrantee, MSc1,2,3; Hyke G. H. Tamminga, MSc1,4; Cheima Bouziane, MSc1,2; Marco A. Bottelier, MD1,5; Esther E. Bron, MSc6,7; Henk-Jan M. M. Mutsaerts, MD, PhD1,2; Aeilko H. Zwinderman, PhD8; Inge R. Groote, PhD9; Serge A. R. B. Rombouts, PhD10,11; Ramon J. L. Lindauer, MD, PhD12,13; Stefan Klein, PhD6; Wiro J. Niessen, PhD6,14; Brent C. Opmeer, PhD15; Frits Boer, MD, PhD12,13; Paul J. Lucassen, PhD16; Susan L. Andersen, PhD17; Hilde M. Geurts, PhD4; Liesbeth Reneman, MD, PhD1,2,3
[+] Author Affiliations
1Department of Radiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
2Brain Imaging Center, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
3Amsterdam Brain and Cognition, University of Amsterdam, Amsterdam, the Netherlands
4d’Arc (Dutch Autism and Attention-Deficit/Hyperactivity Disorder Research Center), Department of Brain and Cognition, University of Amsterdam, Amsterdam, the Netherlands
5Department of Child and Adolescent Psychiatry, Triversum, Alkmaar, the Netherlands
6Biomedical Imaging Group Rotterdam, Department of Medical Informatics, Erasmus Medical Center, Rotterdam, the Netherlands
7Biomedical Imaging Group Rotterdam, Department of Radiology, Erasmus MC, Rotterdam, the Netherlands
8Department of Clinical Epidemiology and Biostatistics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
9Institute of Psychology, Department of Social Sciences, University of Oslo, Oslo, Norway
10Institute of Psychology, Leiden University, Leiden, the Netherlands
11Department of Radiology, Leids Universitair Medisch Centrum, Leiden, the Netherlands
12Department of Child and Adolescent Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
13De Bascule Academic Center for Child and Adolescent Psychiatry, Amsterdam, the Netherlands
14Department of Imaging Physics, Faculty of Applied Sciences, Delft University of Technology, Delft, the Netherlands
15Clinical Research Unit, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
16Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, the Netherlands
17Department of Psychiatry, Harvard Medical School and McLean Hospital, Belmont, Massachusetts
JAMA Psychiatry. 2016;73(9):955-962. doi:10.1001/jamapsychiatry.2016.1572.
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Importance  Although numerous children receive methylphenidate hydrochloride for the treatment of attention-deficit/hyperactivity disorder (ADHD), little is known about age-dependent and possibly lasting effects of methylphenidate on the human dopaminergic system.

Objectives  To determine whether the effects of methylphenidate on the dopaminergic system are modified by age and to test the hypothesis that methylphenidate treatment of young but not adult patients with ADHD induces lasting effects on the cerebral blood flow response to dopamine challenge, a noninvasive probe for dopamine function.

Design, Setting, and Participants  A randomized, double-blind, placebo-controlled trial (Effects of Psychotropic Drugs on Developing Brain–Methylphenidate) among ADHD referral centers in the greater Amsterdam area in the Netherlands between June 1, 2011, and June 15, 2015. Additional inclusion criteria were male sex, age 10 to 12 years or 23 to 40 years, and stimulant treatment–naive status.

Interventions  Treatment with either methylphenidate or a matched placebo for 16 weeks.

Main Outcomes and Measures  Change in the cerebral blood flow response to an acute challenge with methylphenidate, noninvasively assessed using pharmacological magnetic resonance imaging, between baseline and 1 week after treatment. Data were analyzed using intent-to-treat analyses.

Results  Among 131 individuals screened for eligibility, 99 patients met DSM-IV criteria for ADHD, and 50 participants were randomized to receive methylphenidate and 49 to placebo. Sixteen weeks of methylphenidate treatment increased the cerebral blood flow response to methylphenidate within the thalamus (mean difference, 6.5; 95% CI, 0.4-12.6; P = .04) of children aged 10 to 12 years old but not in adults or in the placebo group. In the striatum, the methylphenidate condition differed significantly from placebo in children but not in adults (mean difference, 7.7; 95% CI, 0.7-14.8; P = .03).

Conclusions and Relevance  We confirm preclinical data and demonstrate age-dependent effects of methylphenidate treatment on human extracellular dopamine striatal-thalamic circuitry. Given its societal relevance, these data warrant replication in larger groups with longer follow-up.

Trial Registration  identifier: NL34509.000.10 and trialregister.nl identifier: NTR3103.

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Figure 1.
Consolidated Standards of Reporting Trials Flow Diagram

Patients were randomized to methylphenidate hydrochloride or placebo.

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Figure 2.
Treatment Effects on the Cerebral Blood Flow (CBF) Response to Dopamine Challenge

Shown are the means (SEMs) for the individual change in acute CBF response (Δi CBF) in the placebo and methylphenidate hydrochloride groups.

aP < .05 by independent t test comparing Δi CBF between the 2 treatment groups in the striatum (mean difference, 7.7; 95% CI, 0.7-14.8; P = 0.03, ηp2 = 0.09) (see also Table 2).

bP < .05 by paired t test comparing pretreatment to posttreatment Δi CBF within each group in the thalamus (mean difference, 6.5; 95% CI, 0.4-12.6; P = 0.04, ηp2 = 0.17).

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Figure 3.
Treatment Effects on Global Clinical Impairment in the Methylphenidate and Placebo Groups

Shown are the means (SEMs) for Clinical Global Impression (CGI) scores at baseline, week 3, week 8, and posttreatment (week 17). In children, we found a significant difference between treatment groups in the change from baseline to week 3 (P = .03) and week 8 (P = .005) but not at week 17 (P = .06). In contrast, in adults, we found a significant time × treatment interaction at week 3 (P = .01) and week 17 (P = .01) but not at week 8 (P = .20).

aP < .05 comparing treatment groups on individual time points (by t test).

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